Aroyl-piperidine derivatives

ABSTRACT

The invention relates to novel N-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-4-(quinoloy-lamino)-piperidines of the formula . . . wherein Y and R each are as defined above and the ring A is unsubstituted or mono- or polysubstituted by substituents selected from the group consisting of lower alkyl, lower alkoxy, halogen, nitro and trifluoromethyl; and the salts thereof, to the use thereof, to processes for the preparation thereof and to pharmaceutical compositions comprising a compound according to the invention.

The invention relates to novelN-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-4-(quinoloylamino)-piperidinesof the formula

wherein Y is ═N— or ═N(O)—, R is OH when Y is ═N— and R is H when Y is═N(O)— and the ring A is unsubstituted or mono- or poly-substituted bysubstituents selected from the group consisting of lower alkyl, loweralkoxy, halogen, nitro and trifluoromethyl, provided that when R is OHand Y is ═N— the ring A is not unsubstituted; to the use thereof; toprocesses for the preparation thereof and to pharmaceutical compositionscomprising a compound according to the invention.

Since the compounds according to the invention have at least twooptically active carbon atoms they may accordingly be present in theform of stereoisomers, stereoisomeric mixtures and in the form of the(substantially) pure diastereoisomers. The present invention relatesalso to corresponding stereoisomers.

Preference is given to compounds of formula I wherein the ring A issubstituted.

Unless otherwise defined, the general terms used hereinbefore andhereinafter have the meanings given below.

The term “lower” denotes that groups and compounds so defined each havefrom 1 up to and including 7, preferably from 1 up to and including 4,carbon atoms.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl or a corresponding pentyl,hexyl or heptyl radical. C₁-C₄alkyl is preferred.

Lower alkoxy is, for example, methoxy, ethoxy, n-propyloxy,isopropyloxy, n-butyloxy, iso-butyloxy, sec-butyloxy, tert-butyloxy or acorresponding pentyloxy, hexyloxy or heptyloxy radical C₁-C₄alkoxy ispreferred.

Halogen is especially halogen having an atomic number of up to andincluding 35, i.e. fluorine, chlorine or bromine, and also includesiodine. Chlorine is preferred.

Substance P is a naturally occurring undecapeptide of the tachykininfamily. It is produced in mammals and acts pharmacologically as aneuropeptide. Substance P plays an important role in various disorders,for example in the case of painful conditions, in migraines and incertain disorders of the central nervous system, such as anxiety states,vomiting, schizophrenia and depression, and in certain motor disorders,such as Parkinson's disease, but also in inflammatory diseases, such asrheumatoid arthritis iritis and conjunctivitis, in diseases of therespiratory organs, such as asthma and chronic bronchitis, in diseasesof the gastrointestinal system, such as ulcerative colitis and Crohn'sdisease, and in hypertension.

A great deal of work is being done to advance the development of thefield of substance-P-antagonists and, for example, to find suitablesubstance-P-antagonists having a broad spectrum of action that exhibitoutstanding in vivo activity and increased bioavailability as well asimproved chemical stability.

Extensive pharmacological studies have shown that the compoundsaccording to the invention antagonise substance P to an especiallypreferred extent and thus inhibit the symptoms induced by substance P.

The substance-P-antagonising effects can be demonstrated—as shownbelow—using test methods known to the person skilled in the art. Sucheffects are observed both in vitro and in vivo. For example, thesubstance-P-induced formation of phosphoinositol in human astrocytomacells is antagonised in vitro by the compounds of formula I and IA. IC₅₀values of from approximately 1 nmol are found. A suitable test model forthe detection of that inhibition is, for example, the test method ofLee, C. M. et al., as described in J. Neurochem. 59, 406-414 (1992).

In addition, the binding of ³H-substance P to bovine retina in the radioreceptor assay according to H. Bittiger, Ciba Foundation Symposium 91,196-199 (1982) is inhibited with IC₅₀ values of from approximately 1nmol. For example, the following in vitro values of about 10 nM wereobtained for the target compounds of Examples 1 and 2.

A change in behaviour is produced in gerbils by i.c.v. administration ofsubstance P methyl ester. That effect can be inhibited in vivo afterperoral administration of compounds of formulae I and IA and the saltsthereof. A. Vassout et al. which was presented at the “Substance P andRelated Peptides: Cellular and Molecular Physiology” Congress inWorchester, Mass., in 1990. In that method, ED₅₀values of fromapproximately 0.1 mg/kg p.o. are obtained, demonstrating theirusefulness in the treatment of disorders of the central nervous system.

In vivo, using the experimental procedure of Lundberg et al., Proc. Nat.Acad. Sci. (USA) 80, 1120-1124, the compounds of formulae I and IA andthe salts thereof inhibit vagally induced bronchospasms in guinea pigsat a dose of from approximately 1.0 mg/kg i.v., which demonstrates theirsuitability for the treatment of asthma.

The substance-P-antagonists of formulae I and IA prepared in accordancewith the invention and the pharmaceutically acceptable salts thereof areaccordingly outstandingly suitable for the therapeutic treatment of thepathological symptoms listed hereinbefore.

The invention relates also to a method of treating disorders induced bysubstance P by the administration of a therapeutically effective amountof a compound of formula I or IA.

The present invention relates also to the use of a compound of formula Ior IA in the preparation of medicaments for the treatment of disordersinduced by substance P.

The invention relates also to the use of compounds of formula I or IA asbiochemical tools, for example for the identification and, possibly, theprofiling of further potent substance-P-antagonists.

The invention relates especially to compounds of formula IA

wherein Y and R are as defined above and Z is hydrogen, halogen ornitro, provided that when R is OH and Y is ═N— Z is not H.

The invention relates above all to compounds of formula IA wherein Y andR are defined above and Z is halogen, such as chlorine.

The invention relates specifically to the compounds of formula Imentioned in the Examples.

The invention relates also to processes for the preparation of thecompounds according to the invention. Those processes comprise oxidisinga compound of formula II

and, if desired, separating a mixture of isomers obtainable by theprocess and isolating the desired isomer.

The compound of formula II may be oxidised to give a compound of formulaI; for instance, with 3-chloroperbenzoic acid at room temperature.

Alternatively compounds of formula I in which R is OH and Y is ═N— maybe prepared by linking of the corresponding[(2R,4S)-4-Amino-2-(4-benzyl-piperidin-1-yl]-(3,5-bistrifluormethyl-phenyl)-methanone with 2-hydroxyquinoline-4-carboxylicacid; for instance as hereinafter described in Example 2.

The invention is illustrated especially by the Examples and relates alsoto the novel compounds mentioned in the Examples and to the processesfor the preparation thereof.

The compounds of formula I and IA, may also be obtained in the form ofhydrates or may include the solvent used for crystallisation.

Resulting mixtures of diastereoisomers and mixtures of racemates can beseparated in known manner into the pure diastereoisomers or racemates onthe basis of the physicochemical differences between the constituents,for example by chromatography and/or fractional crystallisation.

Resulting racemates can also be separated into the optical antipodes byknown methods, for example by recrystallisation from an optically activesolvent, with the aid of microorganisms or by reaction of the resultingdiastereoisomeric mixture or racemate with an optically active auxiliarycompound, for example according to the acidic, basic or functionallymodifiable groups present in compounds of formulae I and IA with anoptically active acid, base or an optically active alcohol, intomixtures of diastereoisomeric salts or functional derivatives, such asesters, and separation thereof into the diastereoisomers from which thedesired enantiomer can be freed in the appropriate customary manner.Examples of suitable bases, acids and alcohols are optically activealkaloid bases, such as strychnine, cinchonine or brucine, or D- orL-(1-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetamine and similarsynthetically obtainable bases, optically active carboxylic or sulfonicacids, such as quinic acid or D- or L-tartaric acid, D- orL-di-o-toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid,or D- or L-camphorsulfonic acid, or optically active alcohols, such asborneol or D- or L-(1-phenyl)ethanol.

The novel compounds of formulae I and IA can be used, for example, inthe form of pharmaceutical compositions that comprise a therapeuticallyeffective amount of the active ingredient, optionally together withinorganic or organic, solid or liquid, pharmaceutically acceptablecarriers that are suitable for enteral, for example oral, or parenteraladministration. There are used, for example, tablets or gelatin capsulesthat comprise the active ingredient together with diluents, for examplelactose, dextrose, saccharose, mannitol, sorbitol, cellulose and/orlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium or calcium stearate, and/or polyethylene glycol.Tablets can also comprise binders, for example magnesium aluminiumsilicate, starches, such as corn, wheat, rice or arrowroot starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluloseand/or polyvinylpyrrolidone, and, if desired, disintegrators, forexample starches, agar, alginic acid or a salt thereof, for examplesodium alginate, and/or effervescent mixtures, or absorbents,colourings, flavourings and sweeteners. The novel compounds of formulaeI and IA can also be used in the form of parenterally administrablecompositions or in the form of infusion solutions. Such solutions arepreferably isotonic aqueous solutions or suspensions which, for examplein the case of lyophilised compositions that comprise the activeingredient on its own or together with a carrier, for example mannitol,can be prepared before use. The pharmaceutical compositions may besterilised and/or may comprise excipients, for example preservatives,stabilisers, wetting agents and/or emulsifiers, solubilisers, salts forregulating the osmotic pressure and/or buffers. The pharmaceuticalcompositions in question, which, if desired, may comprise furtherpharmacologically active substances, are prepared in a manner known perse, for example by means of conventional mixing, granulating,confectioning, dissolving or lyophilising processes, and comprise fromapproximately 0.1% to 100%, especially from approximately 1% toapproximately 50%, in the case of lyophilisates up to approximately100%, active ingredient.

The invention relates also to the use of the compounds of formulae I andIA, preferably in the form of pharmaceutical compositions. The dose candepend on various factors, such as the mode of administration, species,age and/or individual condition. The daily doses to be administered are,in the case of oral administration, from approximately 0.25 toapproximately 10 mg/kg, and in the case of warm-blooded animals having abody weight of approximately 70 kg, they are preferably fromapproximately 20 mg to approximately 500 mg.

The following Examples illustrate the invention; temperatures are givenin degrees Celsius and pressures in mbar.

EXAMPLE 1 1-Oxy-quinoline-4-carboxylic acid[(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amide

To a solution of 6.0 g (9.68 mMol) quinoline-4-carboxylic acid[(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amide(Synthesis described in EP 707 006 A) in 60 ml of CH₂Cl₂ were added 2.07g (10.2 mMol) of 3-chloroperbenzoic acid (85%) at room temperature withstirring. After the mixture became homogeneous it was left a roomtemperature for 18 hrs. The mixture was washed successively with 5%aqueous NaHSO₃ and 10% aqueous NaHCO3. The organic phase was dried withK₂CO₃ and concentrated in vacuo. The crude product was recrystallizedfrom MeOH/H₂O. Yield 4.9 g white crystals. Mp. 223-225° C.

MS(ES+): [M+1]⁺=636 and [M+23]⁺=658.

EXAMPLE 2 2-Hydroxy-quinoline-4-carboxylic acid[(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amide

To a stirred mixture of 2.52 g (13.32 mMol)2-hydroxyquinoline-4-carboxylic acid, 2.7 g (15.98 mMol) HOBt (80%), 3.7ml (26.64 mMol) triethylamine and 3.8 g (18.64 mMol) DCC in 50 ml ofCH₂Cl₂ were added at room temperature 12.3 g (13.32 mMol)[(2R,4S)-4-Amino-2-(4-chloro-benzyl)-piperidin-1-yl]-(3,5-bis-trifluoromethyl-phenyl)-methanone(synthesis described in EP 707006A). After 18 h the reaction mixture wasdiluted with 500 ml THF and filtered through a fritted glass funnel withsuction. The filtrate was further diluted with ethyl acetate and washedthree times with brine. The organic phase was dried with Na₂SO₄ andconcentrated in vacuo. The product was purified by chromatography onsilica gel using successively EtOAc/CH₂Cl₂ (2:1), EtOAc and EtOAc/THF(3:1) as eluents. The product was suspended in hexane and stirred at 60°C. overnight. The mixture was filtered and dried and a yield of 6.2 g ofwhite crystals. M.p.222-224° C.

[M+1]⁺=636 and [M+23]⁺=658

EXAMPLE 3

Tablets, each comprising 50 mg of(2R,4S)-N-[1-(3,5-bis-trifluoromethylbenzoyl)-2-benzyl-piperidin-4-yl]quinoline-N-oxide-4-carboxamidecan be prepared as follows:

Composition (10 000 Tablets)

active ingredient 500.0 g lactose 500.0 g potato starch 352.0 g gelatin8.0 g talc 60.0 g magnesium stearate 10.0 g silicon dioxide (highlydispersed) 20.0 g ethanol q.s.

The active ingredient is mixed with the lactose and 292 g of potatostarch and the mixture is moistened with an ethanolic solution of thegelatin and granulated through a sieve. After drying, the remainder ofthe potato starch, the magnesium stearate, the talc and the silicondioxide are mixed in and the mixture is compressed to form tablets, eachweighing 145.0 mg and comprising 50.0 mg of active ingredient; thetablets may, if desired, be provided with breaking notches for fineradaptation of the dose.

EXAMPLE 4

Film-coated tablets, each comprising 100 mg of(2R,4S)-N-[1-(3,5-bis-trifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-3-hydroxy-quinoline-4-carboxamidecan be prepared as follows:

Composition (For 1000 Film-Coated Tablets)

active ingredient 100.0 g lactose 100.0 g corn starch 70.0 g talc 8.5 gcalcium stearate 1.5 g hydroxypropylmethylcellulose 2.36 g shellac 0.64g water q.s. methylene chloride q.s.

The active ingredient, the lactose and 40 g of the corn starch are mixedand moistened with a paste prepared from 15 g of corn starch and water(with heating) and granulated. The granules are dried, the remainder ofthe corn starch, the talcum and the calcium stearate are added and mixedwith the granules. The mixture is compressed to form tablets (weight:280 mg) which are then film-coated with a solution of thehydroxypropylmethylcellulose and the shellac in methylene chloride;final weight of the film-coated tablet: 283 mg.

EXAMPLE 5

Hard gelatin capsules, comprising 100 mg of active ingredient, forexample(2R,4S)-N-[1-(3,5-bis-bifluoromethyl-benzoyl)-2-benzyl-piperidin-4-yl]-quinoline-N-oxide-4-carboxamideor a salt, for example the hydrochloride, thereof, can be prepared, forexample, as follows:

Composition (For 1000 Capsules)

active ingredient 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate  2.0 g magnesium stearate  8.0 g

The sodium lauryl sulfate is added to the lyophilised active ingredientthrough a sieve of 0.2 mm mesh size. The two components are intimatelymixed. Then first the lactose is added through a sieve of 0.6 mm meshsize and then the microcrystalline cellulose is added through a sieve of0.9 mm mesh size. The mixture is then intimately mixed again for 10minutes. Finally the magnesium stearate is added through a sieve of 0.8mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatincapsules are each filled with 390 mg of the resulting formulation.

1. A compound of the formula

wherein Y is ═N— or ═N(O)—, R is OH when Y is ═N— and R is H when Y is═N(O)— and the ring A is unsubstituted or mono- or poly-substituted bysubstituents selected from the group consisting of lower alkyl, loweralkoxy, halogen, nitro and trifluoromethyl, provided that when R is OHand Y is ═N— the ring A is not unsubstituted, and pharmaceuticallyacceptable salts thereof.
 2. A compound according to claim 1 of formula1A

wherein Y is ═N— or ═N(O)—, R is OH when Y is ═N— and R is H when Y is═N(O)—, and Z is hydrogen, halogen or nitro, provided that when R is OHand Y is ═N— Z is not H, and pharmaceutically acceptable salts thereof.3. A compound according to claim 2, wherein Y is ═N— or ═N(O)—, R is OHwhen Y is ═N— and R is H when Y is ═N(O)—, and Z is halogen.
 4. Acompound selected from: 1-oxy-quinoline-4-carboxylic acid[(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)piperidin-4-yl]-amideor a pharmaceutically acceptable salt thereof, or2-hydroxy-quinoline-4-carboxylic acid[(2R,4S)-1-(3,5-bis-trifluoromethyl-benzoyl)-2-(4-chloro-benzyl)-piperidin-4-yl]-amideor a pharmaceutically acceptable salt thereof.
 5. A method of treating acondition characterized by substance-P induction, in an animal in needthereof comprising: administering an amount of substance-P antagonisteffective to inhibit the induction of substance-P, wherein thesubstance-P antagonist is a compound according to claim
 1. 6. Apharmaceutical composition comprising a compound according to claim 1.7. A process for the preparation of a compound of Formula I, comprising:oxidising a compound of formula II;

optionally separating a mixture of isomers obtainable by the process;and isolating the desired isomer of the resulting oxidized compound.